PROJECT SUMMARY Cancer-related fatigue (CRF) is the most frequent and debilitating symptom experienced by prostate cancer patients during and after curative treatment-radiotherapy (RT) and androgen deprivation therapy (ADT), and has detrimental effects on patients' physical, psychological, social, occupational functioning and overall quality of life; however, current treatment options fail to satisfactorily alleviate CRF. Exercise (EX) and Methylphenidate (MP) are by far the most investigated and beneficial therapies for CRF, but both have only modest effects. Based on preliminary data suggesting that the combination of EX plus MP is feasible and may be efficacious in reducing CRF, the proposed research will address the guiding hypothesis that combining EX plus MP will result in a more robust improvement of fatigue using a randomized placebo-controlled trial. The primary objective is to determine if the combination of EX + MP is superior to EX plus placebo in the treatment of CRF in patients with prostate cancer scheduled to receive radiotherapy with androgen deprivation therapy for 12 weeks (Aim 1). CRF will be measured using the area under the curve (AUC) in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale to test the hypothesis that the combination of EX plus MP will result in a greater reduction of CRF compared with exercise plus placebo. To address the hypothesis that the combination of EX plus MP will result in improvements in additional CRF-related measures, the effects of EX plus MP on quality-of-life (using the Functional Assessment of Cancer Therapy ? General), sleep disturbance (using the Pittsburgh Sleep Quality Index and the Multidimensional Fatigue Symptom Inventory), sleep/wake time activity (actigraphy), anxiety and depressed mood (using the Hospital Anxiety and Depression Scale), physical function (using usual gait speed, the 30-second chair stand test, and hand grip strength), cardiorespiratory fitness (VO2 max), inflammation (C-reactive protein), and cognitive measures will be assessed (Aim 2). To address the hypothesis that the combination of methylphenidate plus exercise will have synergistic effects that exceed the reduction in CRF by either exercise alone or methylphenidate alone, potential synergistic effects of EX and MP will be evaluated by measuring the FACIT-F AUC in all four arms, thus informing a model of how EX and MP may interact together (Aim 3). Finally, differences in brain activity between responders and non-responders to the EX plus MP intervention will be explored using electroencephalography (EEG) (Aim 4) in order to identify novel biomarkers of CRF and to inform a new model integrating underlying CRF and its dimensions in response to EX and/or MP. The innovative use of existing technologies, combined with a novel approach to CRF targeting a specific and well-defined patient population, could provide evidence for a safe, feasible, and effective treatment for CRF, and will yield new and highly interpretable data on CRF constituting a significant step forward in the understanding and treatment of fatigue.